Aim 1. 1A. We hypothesize that the premature coronary artery disease, diabetes and stroke of MDD occur as a consequence of the metabolic syndrome in patients with MDD secondary to the CNS changes that promote the cognitive and mood components of MDD. Although the metabolic syndrome occurs in the general population as a consequence of obesity, we have shown that patients with MDD have the six main components of the metabolic syndrome even in the normal weight state. These consist of: (1) activation of the HPA Axis and sympathetic nervous system (protocols 90-M-0199, 88 M-0162) (2) a proinflammatory state (protocol 90-M-0199) (3) insulin resistance with hyperinsulinemia (protocol 00M-0049) (4) increased blood pressure compared to matched controls (protocol 00M-0049) (5) dyslipidemia (protocol 00-M-0049) (6) increased levels of prothrombotic mediators (protocol 00-M-0049) 1B. We hypothesized that the pathophysiological organization of these six stigmata consists of the following cascade that we have documented in MDD, which concluded this year: (note redundant positive feedback loops). We have just finished completing our studies and validated the following: (1) CRH hypersecretion leads to activation of the HPA axis and sympathetic nervous system (protocol 90-M-0199) (2) A proinflammatory state occurs, secondary (paradoxically), in part, to hypercortisolism, which increases the visceral fat mass; visceral fat is replete with proinflammatory mediators like IL-6 that they release into the plasma; IL-6, in turn, stimulates the secretion of proinflammatory acute phase proteins such as CRP from the liver. (Protocol 90-M-0199) (3) Insulin resistance with hyperinsulinemia occurs as a consequence of visceral fat-mediated free fatty acid and inflammatory mediator release, and hypercortisolism. (Protocol 00-M-0049) (4) CRH-mediated activation of the sympathetic nervous system leads to hypertension. Insulin resistance with hyperinmsulinemia and increased inflammatory mediators also stimulate the sympathetic nervous system (protocols 88-M-0162, 90-M-0199, 90-M-0199) (5) Insulin resistance and a proinflammatory state lead to dyslipidemia (protocol 00-M-0049) (6) Finally, a proinflammatory state, insulin resistance, and increased sympathetic outflow each lead independently to a prothrombotic state. (Protocol 04-M-0002) These six pathophysiologic stigmata relating to one another in mutually positive feedback loops promote premature coronary artery disease stroke, and diabetes in patients with MDD. All six are deeply involved in the normal stress response. We have incorporated this model in an invited paper submitted to Molecular Psychiatry entitled, The Organization of the Stress System and Its Dysregulation in Depressive Illness. 1C. We hypothesize that ketamine treatment will ameliorate all six components of the metabolic syndrome in patients with MDD 1D. Available medications like statins can ameliorate the components of the metabolic syndrome through their anti-inflammatory effects and the subsequent amelioration of insulin resistance 1E. We have shown that SSRIs promote insulin resistance by an unknown mechanism, and that lithium promotes insulin resistance by antagonizing adiponectin secretion. Adiponectin is the most potent endogenous stimulus to the impact of insulin at its receptor. (Protocol 04-M-0002) Aim 2. 2A. We previously reported in The New England Journal of Medicine that virtually 30% of premenopausal women with major depression had clinically significant losses of bone that left them with either osteoporosis or osteopenia. The bone loss was greater at the hip than at the spine, an unusual pattern signifying inflammatory mediators rather than hypercortisolism as the primary cause of bone loss in MDD. This finding has been replicated in over 20 other studies. (Conducted under protocol 00-M-0203) 2B. Each of the six factors we identify in the metabolic syndrome of MDD also contributes to the development of osteoporosis. Inflammation, hypercortisolism, and increased sympathetic spillover are especially potent inducers of osteoporosis. Thus, the metabolic syndrome is pathophysiologically linked to osteoporosis in MDD. 2C. Bone strength is a more reliable predictor of bone fracture than bone mineral density. We assessed bone strength by testing load displacement, stiffness, and moment of inertia in Sprague-Dawley rats after 90 days of daily ip injections of antidepressants and anticonvulsants. The antidepressants fluoxetine and imipramine did not affect bone strength, but the anticonvulsants valproic acid and carbamazepine had pronounced effects on multiple parameters of bone strength and by novel means not previously described. Our findings suggest that by not affecting bone strength, antidepressants are not likely to promote bone fracture. Special care should be taken with depressed patients who receive anticonvulsants. (Conducted under Protocol 00-M-0203) 2D. We hypothesize that ketamine will positively affect the balance between markers for bone production vs. bone resorption. Aim 3. Current data suggest a dysregulation in glutamate neurotransmission in depressive illness, and two separate studies have shown an association between affective illness and calcium channel polymorphisms. Calcium is a principal mediator of neuronal glutamate release. We have found that, compared to controls, cerebrospinal fluid (CSF) calcium concentrations are significantly increased in 21 medication-free patients with major depression. This finding potentially reflects increased calcium spillover into CSF, reflecting excessive synaptic calcium concentrations. These patients also had significant decreases in plasma calcium concentrations. The compound klotho, a peripheral and CNS hormonal mediator, plays a significant role in the transfer of calcium from the peripheral circulation to the CSF. We have submitted to Molecular Psychiatry a review paper entitled Klotho: A Humeral Mediator in CSF and Plasma that Influences Longevity and Susceptibility to Multiple Complex Disorders. This paper discusses many of the implications of klotho for health and disease, including its role in bidirectional calcium transfer from the periphery into the CNS. (Protocol 04-M-0002) Clinical Significance of the Findings 1. Patients with MDD have the stigmata of the metabolic syndrome without obesity, indicating an intrinsic cause of the metabolic syndrome secondary to changes in CNS function. Patients with depressive illness should be evaluated for components of the metabolic syndrome, and those who have it should be treated by agents which ameliorate it, such as statins and a member of a group of compounds that have potent effects to increase insulin sensitivity and decrease inflammation. 2. Premenopausal women have a loss in bone mineral density in a pattern that suggests an inflammatory component in its pathophysiology. Our data indicate that given a prevalence of MDD in the 134 million US women between the ages of 21 and 45 years of approximately 16%, we estimate that nearly 4 million premenopausal women with MDD may have undetected deficits in bone mineral density. We now demonstrate that post-menopausal women with major depression have losses of bone that significantly correlated with plasma levels of the inflammatory mediator C-reactive protein, a sensitive marker of inflammation. 3. Further documentation that SSRIs promote insulin resistance would have clinically relevant implications for the many patients on SSRIs. 4. We have advanced the first clinical data supporting a role for a dysregulation in calcium channel function in patients with depressive illness and are investigating potential causes.